The ability to generate cytotoxic T lymphocyte responses to minor H antigens offers a potent tool for the study of self-tolerance and self-recognition. Results obtained in this system have thus far demonstrated 1) that the self + X T cell repetoire is highly cross-reactive for allogeneic MHC determinants suggesting that the response to allogenic MHC antigens is comprised of multiple self + X specificities and 2) that self minor H determinants tolerize T cells only in association with self MHC determinants so that tolerance induction to non-MHC self components is restricted by MHC encoded products. We are currently examining the role of antigen processing in the generation of the cytotoxic response to minor-H antigens. Results so far indicate that 1) Macrophages are requisite for minor H specific CTL generation in vitro. 2) The minor antigens need not be synthesized by the antigen presenting cell but can be acquired in vitro by macrophages and subsequently presented in an immunogenic fashion. 3) The generation of the CTL by non-antigen bearing APC's is inhibitable by antibodies to the T4 molecule expressed by Ia-restricted T helper cells.